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http://dx.doi.org/10.5483/BMBRep.2018.51.12.259

HSP90 inhibitor, AUY922, debilitates intrinsic and acquired lapatinib-resistant HER2-positive gastric cancer cells  

Park, Kang-Seo (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine)
Hong, Yong Sang (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine)
Choi, Junyoung (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine)
Yoon, Shinkyo (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine)
Kang, Jihoon (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine)
Kim, Deokhoon (Asan Institute for Life Science, Department of Pathology, Asan Medical Center)
Lee, Kang-Pa (Department of Biomedical Sciences, University of Ulsan College of Medicine)
Im, Hyeon-Su (Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine)
Lee, Chang Hoon (Bio & Drug Discovery Division, Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology (KRICT))
Seo, Seyoung (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine)
Kim, Sang-We (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine)
Lee, Dae Ho (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine)
Park, Sook Ryun (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine)
Publication Information
BMB Reports / v.51, no.12, 2018 , pp. 660-665 More about this Journal
Abstract
Human epidermal growth factor receptor 2 (HER2) inhibitors, such as trastuzumab and lapatinib are used to treat HER2-positive breast and gastric cancers. However, as with other targeted therapies, intrinsic or acquired resistance to HER2 inhibitors presents unresolved therapeutic problems for HER2-positive gastric cancer. The present study describes investigations with AUY922, a heat shock protein 90 (HSP90) inhibitor, in primary lapatinib-resistant (ESO26 and OE33) and lapatinib-sensitive gastric cancer cells (OE19, N87, and SNU-216) harboring HER2 amplification/over-expression. In order to investigate whether AUY922 could overcome intrinsic and acquired resistance to HER2 inhibitors in HER2-positive gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (OE19/LR and N87/LR) by continuous exposure to lapatinib in vitro. We found that activation of HER2 and protein kinase B (AKT) were key factors in inducing intrinsic and acquired lapatinib-resistant gastric cancer cell lines, and that AUY922 effectively suppressed activation of both HER2 and AKT in acquired lapatinib-resistant gastric cancer cell lines. In conclusion, AUY922 showed a synergistic anti-cancer effect with lapatinib and sensitized gastric cancer cells with intrinsic resistance to lapatinib. Dual inhibition of the HSP90 and HER2 signaling pathways could represent a potent therapeutic strategy to treat HER2-positive gastric cancer with intrinsic and acquired resistance to lapatinib.
Keywords
AUY922; Drug resistance; Gastric cancer; HER2; Lapatinib;
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